Major affective disorders are common, severe, chronic and often a life-threatening illness. Major depression contributes to significant morbidity and mortality. Impairment in physical and social functioning resulting from depression can be just as severe as other chronic medical illnesses. Suicide is the cause of death in 10-20% of individuals with recurrent depressive disorders. Despite the availability of a wide range of antidepressant drugs, clinical trials indicate that 30% to 40% of patients with major depression fail to respond to first-line antidepressant treatment, despite adequate dosage, duration, and compliance. Thus, there is a clear need to develop novel and improved therapeutics for unipolar and bipolar depression. Recent preclinical studies suggest that antidepressants may exert delayed indirect effects on the glutamatergic system. Furthermore, a growing body of data suggests that mood disorders are associated with regional volumetric reductions, and cell loss and atrophy. It is thus noteworthy that lamotrigine, which, among other effects reduces glutamate release, has antidepressant effects, and a pilot study has suggested that NMDA antagonists may have antidepressant effects. Together, this data suggests that the glutamatergic system may play a role in the pathophysiology and treatment of depression and those agents which more directly reduce glutamatergic neurotransmission may represent a novel class of antidepressants. Memantine, an agent approved in Germany for dementia syndrome and Parkinson's disease, has significant antiglutamatergic and neuroprotective properties and may prove to have antidepressant properties in depressed patients. In this study, we propose to investigate the potential efficacy of memantine, which reduces glutamatergic output via open-channel block of the NMDA receptor-associated ion channel. Most importantly, memantine only blocks the channel during periods of abnormal, excessive activity, and leaves relatively spared normal neurotransmission. This finding is the basis for the minimal side effect profile displayed by memantine. Patients, ages 18 to 80, with a diagnosis of major depression (without psychotic features), will be randomized to double-blind treatment to receive either memantine (5-20mg/day) or placebo for a period of 8 weeks. We found that the use of a low- to moderate-affinity NMDA antagonist memantine in doses of 5-20 mg/day was not effective in the treatment of major depressive disorder (Zarate et al in press).